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The House of the Dead is a rail shooter light gun game. Players use a light gun (or mouse, in the PC version) to aim and shoot at approaching zombies. The characters' pistols use magazines which hold 6 rounds; players reload by shooting away from the screen. A set of torches next to the magazine of each player represents remaining health. When a player sustains damage or shoots a hostage, one of their torches is removed. The player dies when all torches are lost. First-aid packs are available throughout the game which restore one torch; some can be obtained from rescued hostages, while others are hidden inside certain breakable objects. Special items can be found within other breakables, granting a bonus to the player who shoots them.

Throughout the course of the game, players are faced with numerous situations in which their action (or inaction) will have an effect on the direction of gameplay. This is exemplified in the opening stage of the game when a hostage is about to be thrown from the bridge to his death. If the player saves the hostage, they will enter the house directly through the front door; however, if the player fails to rescue the hostage, the character is redirected to an underground route through the sewers. If the player rescues all hostages, a secret room full of lives and bonuses is revealed toward the end of the game.

The renowned biochemist and geneticist Roy Curien becomes obsessed with discovering the nature of life and death. While supported by the DBR Corporation and its own team of scientists, Curien's relentless pursuit of this goal slowly drove him insane. His behavior became more erratic and his experiments took a gruesome turn. The Curien Mansion in Europe, which serves as his home and laboratory, experiences an outbreak.

Later in 1998, AMS Agent Thomas Rogan receives a distress call from his fiancée Sophie Richards from the Curien Mansion. Rogan and his partner "G" fly to Europe and arrive at the estate, finding it overrun with undead creatures, which Curien unleashed. A mortally wounded man gives them a journal containing information about Curien's creations and their weaknesses. Rogan and "G" reach Sophie, only to witness her being carried away by a gargoyle-like creature called the Hangedman. They later find Sophie being attacked by the Chariot, a supersoldier wearing armor and armed with a Bardiche. After defeating Chariot, the two attend to Sophie, who seemingly succumbs to her injuries. A furious Rogan goes after the Hangedman. Their pursuit leads Rogan and "G" to the rooftops surrounding the courtyard. After a lengthy battle, they managed to shoot it down.

The two fight their way to find Dr. Curien. The doctor releases the Hermit, a giant spider crab monster, and flees. They manage to kill it, and continue the chase, fighting Chariot and the Hangedman once more. Upon being confronted a second time, Curien unleashes his masterpiece, The Magician, a humanoid creature with pyrokinetic abilities. However, immediately after being released, the Magician reveals himself to be self-aware, refusing to serve any master and kills his creator. Rogan and "G" confront the Magician in one final battle. Before dying, the Magician gives a chilling warning, and explodes. After they give their last remarks, they walk back the entire trail and upon leaving the mansion, they take a final look at it, wherein the view zooms to the entrance doors, which open to reveal Sophie, who survived her injuries. The three then leave the mansion.

Thomas Rogan: A young trained AMS agent who arrives at the Curien Mansion to investigate a series of recent disappearances, alarming events and rescuing missions at the Curien Mansion. His fiancée is Sophie Richards, from whom he receives a distressed phone call, is an employee at the mansion. He, along with Agent G, must hurry to save Rogan's fiancée and, in the process, uncover evidence of depraved scientific endeavor and soon become attestors to the birth of a horrifying evil that must be stopped from leaving the mansion. The character's last name was misspelled as "Rowgun" on the arcade cabinet.

Agent "G": A mysterious AMS agent and Rogan's partner, who accompanies Rogan to the Curien Mansion. If players choose him as the first character, the in-game dialogue in the scene will change, for example, Sophie will address him differently upon arrival at the mansion.

Dr. Roy Curien: An acclaimed biochemist and geneticist who worked for the DBR Corporation and the main antagonist of the game. He was responsible for The Curien Mansion Incident. He was obsessed with discovering the very nature of life and death, which eventually drove him mad. His increasingly questionable methods and experiments garnered the suspicion and alarm of his colleagues, until it was too late. His deteriorating mental state culminated in the creation and wanton release of hideous monsters from the laboratory to the mansion and surrounding estate. Thanks to the efforts of Rogan and G, the creatures were prevented from escaping the mansion grounds.

Sophie Richards: Rogan's fiancée,(After)Beloved Wife. She tried to call Rogan for help upon onset of the disaster. She managed to escape the mansion, but was somehow knocked unconscious and is found by Rogan lying in front of a fountain in the front courtyard. She awakes and runs for Rogan/G but is captured and brought back into the house by The Hanged Man. She is later found in a large room inside the mansion, but is severely wounded by The Chariot. Her survival depends on the rating the player receives upon completion of the game. If the player gets 60,000 score or above, the good ending scene appeared. If below 60,000, she is the undead - the last corpse. While the player's performance would determine her survival in the first game, canonically she survived, married and had a daughter with Rogan, whom they named Lisa Rogan.

The House of the Dead garnered generally positive reviews, the arcade version being held in the highest regard with AllGame awarding it 4.5 out of 5 stars.[13] However, the Saturn and PC versions gained slightly less praise due to their lack of polish, getting "mixed" or "average" reviews according to the review aggregation website GameRankings.[12][11]

When Indianapolis attempted to ban violent video games it argued that The House of the Dead was obscene and so unprotected by the First Amendment. This required U.S. Appeals Court Judge Richard Posner to review the game at length, ultimately finding Indianapolis’ ban was unconstitutional. Unimpressed by the graphics, Judge Posner wrote “The most violent game in the record, "The House of the Dead," depicts zombies being killed flamboyantly, with much severing of limbs and effusion of blood; but so stylized and patently fictitious is the cartoon-like depiction that no one would suppose it "obscene" in the sense in which a photograph of a person being decapitated might be described as "obscene." It will not turn anyone's stomach.”[14]

The game was ported in 1998 to Sega Saturn by Tantalus, and to Windows (PC-CD) by Sega. The conversion suffered from somewhat rushed development.[15] Official Sega Saturn Magazine criticized the graphics and frame-rate of the game, which ran at 20 frames per second. However, extra game modes were added to the port which include a home specific mode that allows the player to select a character; and also a boss battle mode, which pits the player against the game bosses back to back. There isn't a arcade perfect port of the game itself. Today, the arcade version is emulated on the Model 2 emulator.

The Sega Saturn version had a slightly remixed soundtrack, compared to the arcade version of the game. On stage 2, there is a reference to the Space Shuttle Challenger disaster, as the words Challenger, go at throttle up, spoken by Richard O. Covey from the mission control room only seconds before the explosion, can be heard three times before the music loops.[16] While these words do not appear in the arcade version, a snickering laugh can be heard instead.